The tertiary amine nitrogen atom of piperazine sulfonamides as a novel determinant of potent and selective beta3-adrenoceptor agonists.

Novel compounds were prepared in fair to good yields as human beta(3)-adrenoceptor (beta(3)-AR) agonists. In particular, aryloxypropanolamines 7 a-d (EC(50)=0.57-2.1 nM) and arylethanolamines 12 a,b,e (EC(50)=6.38-19.4 nM) were designed to explore the effects of modifications at the right-hand side of these molecules on their activity as beta(3)-AR agonists. Piperidine sulfonamides 15 a-c, e-g (EC(50)=6.1-36.2 nM) and piperazine sulfonamide derivatives 20-29 (EC(50)=1.79-49.3 nM) were examined as compounds bearing a non-aromatic linker on the right- and left-hand sides of the molecules. Some piperazine sulfonamides were found to be potent and selective beta(3)-AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all beta(3)-AR agonists reported so far. (S)-3-{4-{N-{4-{2-[2-Hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl}phenyl}sulfamoyl}phenoxy}propanoic acid (7 d; EC(50)=0.57 nM), (R)-N-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl}-4-(3-octylureido)benzenesulfonamide (12 e; EC(50)=6.38 nM), (R)-2-[1-(4-methoxyphenylsulfonyl)piperidin-4-ylamino]-1-phenylethanol (15 f; EC(50)=6.1 nM), and (S)-4-{2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]propoxy}phenol (25; EC(50)=1.79 nM) were found to be the most potent beta(3)-AR agonists of the aryloxypropanolamine, arylethanolamine, piperidine sulfonamide, and piperazine sulfonamide classes, respectively. The two most potent compounds were identified as possible candidates for further development of beta(3)-AR agonists useful in the treatment of beta(3)-AR-mediated pathological conditions.

Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.

Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.

A chemoenzymatic scalable route to optically active (R)-1-(pyridin-3-yl)-2-aminoethanol, valuable moiety of beta3-adrenergic receptor agonists.

Enantiomerically pure (R)-2-chloro-1-(pyridin-3-yl)ethanol has been prepared by kinetic resolution performed in the presence of Candida antarctica SP435-L lipase immobilized on a macroporous polyacrylate resin (Novozym 435). It was converted into (R)-1-(pyridin-3-yl)-2-aminoethanol, left-hand side of beta(3)-adrenergic receptor ligands.